OBJECTIVE: To examine the effects of an antisense oligodeoxynucleotide (oligo) for human NPY mRNA on in vivo LHRH release. RESULTS Previously, we had shown that NPY plays an important role in pulsatile release of LHRH in vivo in rhesus monkeys 1) NPY release in the stalk-median eminence (S-ME) was pulsatile, 2) direct infusion of NPY to the S-ME increased LHRH release, and 3) direct infusion of an NPY antiserum to the S-ME suppressed LHRH pulses. However, it is unknown how prolonged suppression of NPY release influences LHRH release, since other neurotransmitters/neuromodulators are also involved in control of pulsatile LHRH release. In the present study, we examined the effect of an antisense oligo for human NPY mRNA on in vivo LHRH release using push-pull perfusion in 5 female ovariectomized monkeys. After 6 h of control perfusion, 10 mM of the NPY antisense oligo was infused for 8 h, which was followed by an additional 4 h of control perfusion. For a control, an oligodeoxynucleotide containing the same bases in a scrambled sequence was similarly examined. LHRH and NPY levels in perfusate samples, collected in 10-min fractions were measured by RIA. NPY antisense oligo infusion resulted in a significant decrease in NPY release starting 2 h after the initiation of infusion, and continuing until shortly after the end of antisense oligo infusion (p<0.05, n=5), whereas the scrambled oligo infusion did not result in any changes in NPY release. NPY antisense oligo also suppressed LHRH release (P<0.05, n=5) The NPY antisense oligo induced an LHRH suppression starting 4 h after the initiation of infusion, and continued for the entire period of the experiment. No LHRH suppression was induced by the scrambled oligo. Interestingly, the synchronization of LHRH pulses and NPY pulses, observed before the NPY antisense oligo infusion, was no longer detected 2h after the initiation of antisense oligo infusion. FUTURE DIRECTIONS We will examine the role of Y1 NPY receptors. KEY WORDS pulsatile NPY release, pulsatile LHRH release, antisense NPY mRNA.